rs4939883 — LOC105372112

The Endothelial Lipase Locus — A Regulatory Driver of Your HDL

Your HDL cholesterol is not a fixed trait — it is shaped moment to moment by enzymes that dismantle and rebuild lipoprotein particles circulating in your bloodstream. Endothelial lipase (EL)¹¹ Endothelial lipase (EL)
An enzyme encoded by the LIPG gene on chromosome 18, secreted specifically from vascular endothelial cells; the primary enzyme responsible for phospholipid hydrolysis on the HDL particle surface is the dominant enzymatic brake on HDL levels — the more EL circulates, the faster HDL particles are catabolized and cleared. rs4939883 is an intronic variant in LOC105372112, a gene immediately adjacent to LIPG, that tags a regulatory element controlling how much endothelial lipase your body produces. The T allele at this position is associated with higher circulating EL and, as a consequence, measurably lower HDL cholesterol at genome-wide significance across tens of thousands of participants.

The Mechanism

rs4939883 lies within an intron of LOC105372112, an uncharacterized locus flanking LIPG at chromosome 18q21. The variant does not alter any protein sequence. Instead, it tags a regulatory haplotype spanning the LIPG locus that influences endothelial lipase expression. Carriers of the T allele show measurably higher plasma EL concentrations: in the SIRCA study (n=755), mean plasma EL increased from 481.8 ng/mL in CC homozygotes to 538.8 ng/mL in CT heterozygotes to 772.9 ng/mL in TT homozygotes²² mean plasma EL increased from 481.8 ng/mL in CC homozygotes to 538.8 ng/mL in CT heterozygotes to 772.9 ng/mL in TT homozygotes
Data from Khetarpal et al. PLoS Genetics 2011; PMID 22174694 — a near-doubling in the homozygous state. The mechanism runs directly through EL biology: higher EL expression → faster phospholipid hydrolysis of the HDL surface coat → smaller, cholesterol-depleted HDL particles → accelerated renal clearance → lower HDL-C measured on a blood test. Each step is mechanistically established.

The variant is in linkage disequilibrium with rs2156552 and rs7241918, other LIPG locus tag SNPs that show overlapping HDL-C associations. It shares the same regulatory neighborhood as rs2000813³³ rs2000813
The LIPG Thr111Ile coding variant whose HDL association is attributable to LD with regulatory elements rather than a change in enzyme function, but rs4939883 sits in a different region and may tag a distinct regulatory element affecting EL expression more directly.

The Evidence

The GLGC (Global Lipids Genetics Consortium)⁴⁴ GLGC (Global Lipids Genetics Consortium)
A large international consortium combining GWAS data from dozens of cohorts and hundreds of thousands of participants across multiple ancestries has catalogued rs4939883 associations with HDL-C at p-values ranging from 10⁻⁷ to 10⁻⁴⁵ across multiple independent studies. In one of the largest analyses (GCST007140, combined multi-ethnic sample), the T allele was associated with 0.064 mmol/L lower HDL-C (p = 10⁻⁴⁵) in the European stratum and 0.084 mmol/L lower in Hispanic participants.

Khetarpal et al. (2011)⁵⁵ Khetarpal et al. (2011)
Mining the LIPG Allelic Spectrum Reveals the Contribution of Rare and Common Regulatory Variants to HDL Cholesterol. PLoS Genetics directly measured plasma endothelial lipase concentrations alongside genotype, finding the T allele associated with both lower HDL-C (−0.16 SD, p = 2.28×10⁻⁷) and higher plasma EL (p = 1.43×10⁻³) in the Framingham Heart Study, establishing the mechanistic link — not just statistical association — between this variant and EL expression.

Yang et al. (2019)⁶⁶ Yang et al. (2019)
Association between LIPG polymorphisms and serum lipid levels in Maonan and Han populations. J Gene Med replicated the association in 1,483 Chinese adults across two ethnic groups. T allele carriers had significantly higher ApoB in the Han population and lower HDL-C in the Maonan minority, with both associations surviving Bonferroni correction. The study also found that allele frequencies differed significantly between the two ethnic groups (T = 19.3% in Han vs 23.5% in Maonan; p < 0.01), underscoring that the variant's frequency — and therefore population-attributable effect — varies by ancestry. African-ancestry populations carry the T allele at nearly 45%, making this locus a particularly important HDL determinant in that population.

Practical Actions

For CC homozygotes — the most common genotype — endothelial lipase expression is at its lowest for this locus, providing a structural advantage for maintaining higher HDL. For CT and TT carriers, the increase in EL expression means HDL particles are being catabolized more quickly. The most actionable dietary response to elevated EL activity is targeting EL's anti-inflammatory regulation: LIPG expression is upregulated by pro-inflammatory cytokines (particularly TNF-α and IL-1β), so any strategy that durably lowers systemic inflammation can blunt EL-driven HDL catabolism in carriers. Omega-3 fatty acids (EPA and DHA) both reduce inflammatory EL upregulation and improve HDL particle remodeling via independent mechanisms, making them the highest-value supplement for this genotype.

Interactions

rs4939883 and rs2000813 are both tag SNPs for the same LIPG regulatory region, but they are not in perfect LD and may capture independent variation in EL expression. A user carrying the T allele at rs4939883 (higher EL expression) AND the CC genotype at rs2000813 (lacking the expression-reducing haplotype of that locus) would have a double-disadvantage for HDL: elevated EL from both regulatory mechanisms acting independently. Conversely, the T allele at rs2000813 (which tags a haplotype that reduces LIPG 5'UTR activity) might partially offset the EL-raising effect of rs4939883-T. rs2278236 in ANGPTL4 encodes a direct inhibitor of endothelial lipase; carriers of the reduced-function ANGPTL4 allele alongside rs4939883-T face compounded EL activity from both reduced inhibition and elevated expression.